Brian H. Warrington

Synthesis and analysis of combinatorial libraries performed in an automated micro reactor system

This paper presents the synthesis of combinatorial libraries performed on a single-channel glass micro reactor under hydrodynamic flow control. The experiments were carried out in a non-well based micro chip and consisted of the preparation of libraries of pyrazoles by means of a Knorr reaction of 1,3-dicarbonyl compounds with hydrazines. The aim of this work is to investigate the capabilities of an automated micro reactor based system to synthesise sequentially multiple analogue reactions. Small slugs of reactants were introduced automatically by an autosampler in a serpentine-etched glass chip. The mobility of the reagents and products was achieved using hydrodynamic driven flow. Reaction slug dilution and UV slug detection took place at the outlet. A sample of the slug was analysed by using an on-line LC-UV-MS system. The degree of conversion was quantified using the UV signal and comparing with standards of starting materials and final products. After the LC-UV-MS analysis, the automated system proceeds to inject the slugs to carry out the next reaction programmed. The results suggest that the micro reactor system is capable of repeating the process of injection, mixing and reaction in an automated manner as many times as required.

A Hantzsch synthesis of 2-aminothiazoles performed in a heated microreactor system.

This paper presents the first example known to the authors of a heated organic reaction performed on a glass microreactor under electro-osmotic flow control. The experiments consisted of the preparation of a series of 2-aminothiazoles by means of a Hantzsch reaction of ring-substituted 2-bromoacetophenones and 1-substituted-2-thioureas carried out in microchannels, with the aim of investigating the generic utility of the reactor in carrying out analogue reactions. The reactions were performed on T-design microchips etched into a thin borosilicate glass plate and sealed over with a thick borosilicate top plate containing reservoirs. The mobility of the reagents and products was achieved using electro-osmotic flow (EOF), with the driving voltages being generated by a computer-controlled power supply. During the experiments the T-shaped chip was heated at 70 C using a Peltier heater, aligned with the channels and the heat generated by this device was applied to the lower plate. The degree of conversion was quantified by LC-MS using UV detection by comparison with standard calibration curves for starting materials and final products. In all cases, conversions were found to be similar or greater than those found for equivalent macro scale batch syntheses, thus illustrating the potential of this heated microreactor system to generate a series of compounds which contain biologically active molecules.

The generation of concentration gradients usingelectroosmotic flow in micro reactors allowing stereoselective chemicalsynthesis

The stereoselective control of chemical reactions has been achieved by applying electrical fields in a micro reactor generating controlled concentration gradients of the reagent streams. The chemistry based upon well-established Wittig synthesis was carried out in a micro reactor device fabricated in borosilicate glass using photolithographic and wet etching techniques. The selectivity of the cis (Z) to trans (E) isomeric ratio in the product synthesised was controlled by varying the applied voltages to the reagent reservoirs within the micro reactor. This subsequently altered the relative reagent concentrations within the device resulting in Z/E ratios in the range 0.57-5.21. By comparison, a traditional batch method based on the same reaction length, concentration, solvent and stoichiometry (i.e., 1.0:1.5:1.0 reagent ratios) gave a Z/E in the range 2.8-3.0. However, when the stoichiometric ratios were varied up to ten times as much, the Z/E ratios varied in accordance to the micro reactor i.e., when the aldehyde is in excess, the Z isomer predominates whereas when the aldehyde is in low concentrations, the E isomer is the more favourable form. Thus indicating that localised concentration gradients generated by careful flow control due to the diffusion limited non-turbulent mixing regime within a micro reactor, leads to the observed stereo selectivity for the cis and trans isomers.

Synthesis of a three-member array of cycloadducts in a glass microchip under pressure driven flow

The synthesis of a series of cycloadduct products carried out in a glass microchip under pressure driven flow is presented. Initially, four different compounds were synthesized individually with conversions similar to those obtained in the corresponding batch macroscale reactions. Using identical experimental conditions for all four compounds, the results were highly predictable and reproducible, without the need for individual optimization. A multi-reaction experiment was then carried out in a single chip achieving the synthesis of a three-member array in a single run.

Polymer-assisted solution phase synthesis of the antihyperglycemic agent Rosiglitazone (Avandia™)

The commercially important antihyperglycemic agent Rosiglitazone 1(Avandia) has been prepared in high purity by a multi-step, polymer-assisted solution phase (PASP) synthesis without the need for the conventional chromatographic purification of any intermediates.

A novel phase-switching protecting group for multi-step parallel solution phase synthesis

A new phase-tag 1 which facilitates the parallel solution phase synthesis of carboxylic acids, esters, and carboxamides is reported. The new phase tag assists compound purification by enabling the selective resin capture of reaction products in either a reversible pH dependent manner (solid-phase extraction), or irreversibly in a Diels-Alder reaction.

The Design of a Continuous Flow Combinatorial Screening Micro Reactor System with On-Chip Detection

A micro reactor device has been developed which enables the synthesis of a number of nitro stilbene esters to be carried out using electroosmotic flow (EOF) as the mobilisation mechanism. The micro reactor was fabricated from borosilicate glass using photolithography and wet etching techniques generating an array of interconnecting channels. The micro reactor device was optimised using Wittig chemistry that allowed analogue synthesis of a number of aldehydes generating a generic methodology. Currently, work is continuing to automate and develop the micro reactor allowing in-situ detection to be coupled to the system, thus increasing the drug development and screening flexibility.

A Combinatorial Library of Pyrazoles Performed in an Automated Micro Reactor System

This paper reports a combinatorial library synthesis, detection and analysis carried out in an automated micro reactor system. The reactions were performed in a non-well based glass micro channel reactor. The results demonstrate the ability of a single micro reactor to carry out combinatorial chemistry.

A Micro Reactor Device for the Ugi Four Component Condensation (4CC) Reaction

This paper describes a micro reactor system, in which the solution phase Ugi four-component condensation (4CC) reaction was investigated. The micro reactor is the first of its kind to perform the Ugi reaction on-chip using electro osmotic flow (EOF) producing the reaction intermediate in-situ. Currently, the reaction intermediate (an imine) can be synthesised successfully to a maximum yield of 94.3±4.4% (n=12) with a conversion to the final product of 60%. However, research is continuing into the final stage of the reaction to improve the reactions reproducibility.